Hyperlipidemia, a risk factor for cardiovascular disease, is defined as pathologically elevated plasma concentrations of cholesterol and other lipids, which are commonly found in patients with atherosclerosis (Libby et al., 2011, Nature 473:317-25). It has been reported that hyperlipidemia, proinflammatory mediators, and other risk factors promote endothelial cell (EC) activation and atherosclerosis via several mechanisms, which include inducing endothelial activation and injury (Mestas and Ley, 2008, Trends Cardiovasc Med 18:228-32; Jiang et al., 2005, Arterioscler Thromb Vasc Biol 24:2515-21), increasing monocyte recruitment and differentiation (Zhang et al., 2009, Circulation 120:1893-902; Combadière et al., 2008, Circulation 117:1649-57), and decreasing regulatory T cell population (Xiong et al., 2009, Atherosclerosis. 203:401-8: Ait-Oufella et al., 2006, Nat Med 12:178-80).
ECs that line the inner surface of vessel wall are the first cells exposed to metabolite-related endogenous danger signals in the circulatory system (Libby et al., 2011, Nature 473:317-25). Endothelial activation is, therefore, defined as the initial event responsible for monocyte recruitment in atherogenesis (Chowienczyk et al., 1992, Lancet 340:1430-2). However, questions such as how hyperlipidemia can be sensed by ECs and how hyperlipidemia-induced vascular inflammation is initiated remain largely unanswered.
The cellular receptors, which can recognize the risk factors for atherogenesis, such as hyperlipidemia, have been under intensive search. The role of receptors for pathogen-associated molecular patterns has been characterized recently as bridging innate immune sensory systems for exogenous infectious agents and endogenous metabolic danger signals associated molecular patterns (DAMPs) to initiation of inflammation (Yang et al., 2008, Drug Discov Today Ther Strateg 5:125-42). The toll-like receptors, mainly located in the plasma membrane, recognize a variety of conserved microbial pathogen-associated molecular patterns and metabolic DAMPs and promote inflammatory gene transcription. As we described previously (Yin et al., 2009, Int J Immunopathol Pharmacol 22:311-22), for inflammation-privileged tissues in which inflammasome component genes are not constitutively expressed, toll-like receptors also work in synergy with cytosolic sensing receptor families, including nod-like receptors (NLRs; NOD [nucleotide binding and oligomerization domain]-like receptors) in recognizing endogenous DAMPs and in mediating upregulation and activation of a range of inflammatory genes (Yin et al., 2013, Front Biosci 18:638-49). Caspase-1, a member of the cysteine protease family of caspases, is present in the cell cytosol as pro-caspase-1, an inactive zymogen, and requires the assembly of an NLR family member-containing protein complex called inflammasome for activation. Activated caspase-1 is required for cleaving/processing pro-interleukin-1β (IL-1β) and pro-IL-18 into mature proinflammatory cytokines IL-1β and IL-18, respectively, and activation of other inflammatory pathways. However, it remains unclear whether in early atherosclerosis, the caspase-1-inflammasome pathway in ECs can sense elevated lipids as a DAMP and promote endothelial activation.
Previous reports showed that cholesterol crystals activate NLRP3 inflammasome in macrophages (Duewell et al., 2010, Nature 464:1357-61; Rajamäki, 2010, PLoS One 5:e11765), suggesting that NLRP3 inflammasome in macrophages can sense cholesterol crystals formed in advanced stage of atherosclerosis (Lim et al., 2011, J Limpid Res 52:2177-86). However, monocyte migration into the aorta after 3 weeks of high fat (HF) diet feeding is detected in atherosclerotic apolipoprotein E (ApoE)−/− mice (Nakashima et al., 1994, Arterioscler Thromb 14:133-40), suggesting that before cholesterol crystal formation in the vessels, ECs may respond to hyperlipidemia and activate caspase-1 precedent for monocyte recruitment. It has been reported that in response to various proinflammatory stimuli, including lipopolysaccharide, human ECs secrete IL-1β, resulted from the cleavage of pro-IL-1β by activated caspase-1. However, IL-1β secretion from human ECs, detected by ELISA, are 70.6-folds lower than that secreted from human monocytes (Wilson et al., 2007, Br J Pharmacol 151:115-27), suggesting that IL-1β role in ECs as functional consequence of caspase-1 activation may not be as significant as that in monocytes. Thus, additional roles of caspase-1 in ECs need to be further explored. Although proatherogenic functions of caspase-1 (Gage et al., 2012, Can J Cardiol 28:222-9), NLRP3 (Duewell et al., 2010, Nature 464:1357-61), IL-1β (Merhi-Soussi et al., 2005, Cardiovasc Res 66:583-93), and IL-18 (Whitman et al., 2002, Circ Res 30:E34-8) have been reported, important knowledge gaps remain, such as (1) whether caspase-1 sensing system in ECs can sense early hyperlipidemia (noncholesterol crystals lipid stimulus) and (2) whether caspase-1 activation in ECs can promote endothelial activation, monocyte recruitment, and atherogenesis.
It has been reported that caspase-1 can have >70 protein substrates (Shen et al., 2010, Atherosclerosis 201:422-9), the list of which is getting longer. A recent report showed that caspase-1 specifically cleaves sirtuin 1 (Sirt1), a nicotinamide adenine dinucleotide-dependent protein/class III histone deacetylase, in adipose tissue during metabolic stress (Chalkiadaki and Guarente, 2012, Cell Metab 16:180-8). However, the question of whether caspase-1 cleaves Sirt1 in aortic ECs remains unanswered.
Thus, there is a need in the art for compositions and methods for treating hyperlipidemia. The present invention satisfies this unmet need.